[go: up one dir, main page]

US20230150952A1 - Type 2 ryanodine receptor activity inhibitor - Google Patents

Type 2 ryanodine receptor activity inhibitor Download PDF

Info

Publication number
US20230150952A1
US20230150952A1 US17/760,419 US202117760419A US2023150952A1 US 20230150952 A1 US20230150952 A1 US 20230150952A1 US 202117760419 A US202117760419 A US 202117760419A US 2023150952 A1 US2023150952 A1 US 2023150952A1
Authority
US
United States
Prior art keywords
ring
group
carbon atoms
substituted
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
US17/760,419
Other languages
English (en)
Inventor
Nagomi Kurebayashi KUNIHIRO
Takashi Murayama
Hiroyuki Kagechika
Shuichi Mori
Mari Yuasa
Hiroto IINUMA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Juntendo Educational Foundation
Original Assignee
Juntendo Educational Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Juntendo Educational Foundation filed Critical Juntendo Educational Foundation
Assigned to JUNTENDO EDUCATIONAL FOUNDATION reassignment JUNTENDO EDUCATIONAL FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MORI, SHUICHI, YUASA, MARI, IINUMA, Hiroto, KAGECHIKA, HIROYUKI, KUNIHIRO, Nagomi Kurebayashi, MURAYAMA, TAKASHI
Publication of US20230150952A1 publication Critical patent/US20230150952A1/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a type 2 ryanodine receptor activity inhibitor. More specifically, the present invention relates to type 2 ryanodine receptor activity inhibitor, a medicament, a tetrazole compound and others.
  • a ryanodine receptor is a Ca 2+ release channel, responsive for calcium ion (Ca 2+ ) release from sarcoplasmic reticulum (SR), which is an indispensable step for muscle contraction.
  • RyR opens to release Ca 2+ into the cytoplasmic matrix upon receiving stimulation of Ca 2+ from the cytoplasmic matrix (Ca 2+ -induced Ca 2+ release, CICR).
  • the working mechanism of RyR is positive feedback. More specifically, a small amount of Ca 2+ present in the cytoplasmic matrix near the channel induces release of a large amount of Ca 2+ from SR.
  • RyRs are classified into RyR1 (type 1 ryanodine receptor), which is primarily expressed in skeletal muscle, RyR2 (type 2 ryanodine receptor), which is primarily expressed in myocardium, and RyR3 (type 3 ryanodine receptor), which is widely expressed in the brain.
  • RyR1 type 1 ryanodine receptor
  • RyR2 type 2 ryanodine receptor
  • RyR3 type 3 ryanodine receptor
  • RyR2 Mutations in RyR2 gene elevate CICR activity abnormally and cause diseases such as catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy and mental retardation. Even in the case of wild-type RyR2, abnormal activation of RyR2 occurs due to e.g., excessive phosphorylation and causes diseases such as chronic heart failure and Alzheimer's disease (for example, e.g., Non Patent Literatures 1 to 6).
  • an object of the present invention is to provide a RyR2 activity inhibitor having an excellent RyR2 activity inhibitory effect.
  • the present inventors separately cultivated cultured cells expressing a fluorescent endoplasmic reticulum Ca 2+ indicator and a disease-linked mutant RyR, and cultured cells expressing a fluorescent endoplasmic reticulum Ca 2+ indicator and a wild type RyR, measured the Ca 2+ concentration in the endoplasmic reticulum in the presence of a test substance, and compared the Ca 2+ concentrations in the endoplasmic reticulum of both cultured cells.
  • CICR activity inhibitors more specifically, drugs for preventing or treating diseases associated with abnormally elevated ryanodine receptor activity, can be screened (Non Patent Literature 7) and previously filed a patent application (JP Patent Application No. 2016-113147).
  • the present invention provides the following ⁇ 1> to ⁇ 12>.
  • a type 2 ryanodine receptor activity inhibitor (hereinafter referred to as a type 2 ryanodine receptor activity inhibitor of the present invention or a RyR2 activity inhibitor of the present invention) comprising a compound represented by the following formula ( ⁇ 1) or a salt thereof, or a solvate of the compound or a salt thereof (hereinafter, these will be sometimes collectively referred to as “compound ( ⁇ 1)”),
  • ring Q 1 and ring Q 2 each independently represent a condensed ring of a monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring, or a benzene ring,
  • R 1 and R 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group or a halogen atom,
  • R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms
  • R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms
  • X represents an oxygen atom or a sulfur atom
  • Y represents a methine group or a nitrogen atom
  • n and m each independently represent an integer of 0 to 5;
  • n number of R 1 may be the same or different and two R 1 may join together to form a ring; and if m is an integer of 2 to 5, m number of R 2 may be the same or different and two R 2 may join together to form a ring.
  • ring Q 1 and ring Q 2 are each independently a condensed ring of a 4 to 8 membered oxygen-containing monocyclic heterocycle and a benzene ring, or a benzene ring.
  • R 1 and R 2 are each independently a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, a cyano group or a halogen atom.
  • ⁇ 4> The type 2 ryanodine receptor activity inhibitor according to any one of ⁇ 1> to ⁇ 3>, wherein R 4 is an alkanediyl group having 1 to 3 carbon atoms or an alkenediyl group having 2 to 8 carbon atoms.
  • ⁇ 5> The type 2 ryanodine receptor activity inhibitor according to any one of ⁇ 1> to ⁇ 4>, wherein R 3 is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 9 carbon atoms or a substituted or unsubstituted alkenyl group having 2 to 5 carbon atoms.
  • ⁇ 6> The type 2 ryanodine receptor activity inhibitor according to any one of ⁇ 1> to ⁇ 5>, wherein R 3 is a methyl group.
  • n is an integer of 1 to 5.
  • ⁇ 8> The type 2 ryanodine receptor activity inhibitor according to any one of ⁇ 1> to ⁇ 7>, wherein m is an integer of 1 to 5.
  • a medicament for preventing or treating a disease associated with abnormally elevated type 2 ryanodine receptor activity, comprising a compound represented by the above formula ( ⁇ 1) or a salt thereof, or a solvate of the compound or a salt thereof.
  • the disease associated with abnormally elevated type 2 ryanodine receptor activity is a disease selected from the group consisting of catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy, mental retardation, chronic heart failure and Alzheimer's disease.
  • ring Q 1 and ring Q 2 each independently represent a condensed ring of a monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring, or a benzene ring,
  • R 1 and R 2 each independently represent a substituted or unsubstituted hydrocarbon group having 1 to 3 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group or a halogen atom,
  • R 3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group having 1 to 8 carbon atoms
  • R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms
  • X represents an oxygen atom or a sulfur atom
  • Y represents a methine group or a nitrogen atom
  • n and m each independently represent an integer of 1 to 5;
  • n number of R 1 may be the same or different and two R 1 may join together to form a ring; and if m is an integer of 2 to 5, m number of R 2 may be the same or different and two R 2 may join together to form a ring.
  • a method for inhibiting a type 2 ryanodine receptor activity comprising a step of administering a compound represented by the above formula ( ⁇ 1) or a salt thereof, or a solvate of the compound or a salt thereof.
  • a method for preventing or treating a disease associated with abnormally elevated type 2 ryanodine receptor activity comprising a step of administering a compound represented by the above formula ( ⁇ 1) or a salt thereof, or a solvate of the compound or a salt thereof.
  • a compound represented by formula ( ⁇ 1) or a salt thereof, or a solvate of the compound or a salt thereof has an excellent RyR2 activity inhibitory effect and is useful as a medicament preventing or treating diseases associated with abnormally elevated RyR2 activity.
  • the compounds ( ⁇ 2) to ( ⁇ 12) of the present invention are novel compounds having an excellent RyR2 activity inhibitory effect.
  • FIG. 1 An electrocardiogram of a mouse harboring RyR2 mutation before and after administration of compound 57.
  • FIG. 2 A graph showing the effect of compound 57 on occurrence of arrhythmia of mice harboring RyR2 mutation at a normal time.
  • the type 2 ryanodine receptor activity inhibitor and a medicament of the present invention contain a compound represented by the following formula ( ⁇ 1) or a salt thereof, or a solvate of the compound or a salt thereof. It has not been known that a compound represented by formula ( ⁇ 1) or a salt thereof, or a solvate of the compound or a salt thereof has a RyR2 activity inhibitory effect, and is useful as a drug for preventing or treating diseases associated with abnormally elevated RyR2 activity. Note that, in the specification, the “preventing or treating” diseases includes use for not only preventing or treatment diseases but also both preventing and treating diseases.
  • ring Q 1 and ring Q 2 each independently represent a condensed ring of a monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring, or a benzene ring,
  • R 1 and R 2 each independently represent a substituted or non-substituted hydrocarbon group having 1 to 8 carbon atoms, a substituted or non-substituted alkoxy group having 1 to 8 carbon atoms, a substituted or non-substituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or non-substituted alkanoyl group having 2 to 2 carbon atoms, a substituted or non-substituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom,
  • X represents an oxygen atom or a sulfur atom
  • Y represents a methine group or a nitrogen atom
  • n and m each independently represent an integer of 0 to 5;
  • n number of R 1 may be the same or different and two R 1 may join together to form a ring.
  • m number of R 2 may be the same or different and two R 2 may join together to form a ring.
  • Y represents a methine group or a nitrogen atom.
  • Y is preferably a nitrogen atom.
  • ring Q 1 and ring Q 2 each independently represent a condensed ring of a monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring, or a benzene ring.
  • the above monocyclic heterocycle is preferably a 4 to 5 membered monocyclic heterocycle, more preferably a 5 to 7 membered monocyclic heterocycle, and particularly preferably, a 5 to 6 membered monocyclic heterocycle.
  • a monocyclic heterocycle containing one or more heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom is mentioned.
  • An oxygen-containing monocyclic heterocycle is preferable and a 4 to e membered oxygen-containing monocyclic heterocycle is more preferable.
  • Examples of the monocyclic heterocycle include an oxetane ring, dioxolane ring, a dioxane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydrothiophene ring, a tetrahydrothiopyran ring, a pyrrolidine ring, a piperidine ring, a piperazine ring and a morpholine ring.
  • an oxetane ring, a dioxolane ring and a dioxane ring are preferable.
  • Examples of the condensed ring of a monocyclic heterocycle and a benzene ring include a 7-oxabicyclo[4.2.0]octa-1(6), 2,4-triene ring, a 1,3-benzodioxole ring and a 1,4-benzodioxane ring.
  • the monocyclic carbon ring is preferably a 4 to 9 membered monocyclic carbocyclic ring, and more preferably, a 5 to 7 membered monocyclic carbocyclic ring.
  • Examples of the condensed ring of a monocyclic carbocyclic ring and a benzene ring include an indane ring and a tetralin ring.
  • ring Q 1 is a condensed ring of a monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring
  • the binding site of Y and an adjacent carbon atom in formulas ( ⁇ 1) and ( ⁇ 2) is not particularly limited, and a monocyclic heterocycle, a monocyclic carbocyclic ring or a benzene ring contained in a condensed ring may be acceptable and a benzene ring contained in a condensed ring is preferable.
  • ring Q 2 is a condensed ring of a monocyclic heterocycle or monocyclic carbocyclic ring and a benzene ring
  • the binding site of R 3 and an adjacent nitrogen atom in formulas ( ⁇ 1) and ( ⁇ 2) is not particularly limited, and a monocyclic heterocycle, a monocyclic carbocyclic ring or a benzene ring contained in a condensed ring is acceptable and a benzene ring contained in a condensed ring is preferable.
  • Ring Q 1 and ring Q 2 are, in view of the RyR2 activity inhibitory effect, preferably a condensed ring of a monocyclic heterocycle and a benzene ring, and a benzene ring; and more preferably, a condensed ring of a 4 to 8 membered oxygen-containing monocyclic heterocycle and a benzene ring, and a benzene ring.
  • ring Q 1 is, in view of the RyR2 activity inhibitory effect, particularly preferably a benzene ring.
  • ring Q 2 is, in view of the RyR2 activity inhibitory effect, particularly preferably a 1,3-benzodioxole ring or a benzene ring.
  • R 1 and R 2 each independently represent a substituted or non-substituted hydrocarbon group having 1 to 2 carbon atoms, a substituted or non-substituted alkoxy group having 1 to 8 carbon atoms, a substituted or non-substituted alkoxycarbonyl group having 2 to 8 carbon atoms, a substituted or non-substituted alkanoyl group having 2 to 8 carbon atoms, a substituted or non-substituted alkanoyloxy group having 2 to 8 carbon atoms, a hydroxy group, a cyano group, or a halogen atom.
  • R 3 represents a hydrogen atom or a substituted or non-substituted hydrocarbon group having 1 to 8 carbon atoms.
  • hydrocarbon group represented by each of R 1 , R 2 and R 3 , includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group and an aromatic hydrocarbon group, and is preferably an aliphatic hydrocarbon group.
  • the aliphatic hydrocarbon group may be linear or branched or saturated or unsaturated.
  • Examples of the aliphatic hydrocarbon group include an alkyl group, an alkenyl group and an alkynyl group. Of them, in view of the RyR2 activity inhibitory effect, an alkyl group and an alkenyl group are preferable, and an alkyl group is more preferable.
  • the number of carbon atoms of an alkyl group is, in view of the RyR2 activity inhibitory effect, preferably 1 to 8, more preferably 1 to 4, further preferably 1 to 3, and particularly preferably 1.
  • the alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and a hexyl group. Of them, in view of the RyR2 activity inhibitory effect, a methyl group, an ethyl group, a n-propyl group and an isopropyl group are preferable, and a methyl group is particularly preferable.
  • the number of carbon atoms of an alkenyl group and an alkynyl group is preferably 2 to 8, more preferably 2 to 4, and particularly preferably 2 to 3.
  • alkenyl group include an ethenyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 1,3-butadienyl group, a 1-pentenyl group, 2-pentenyl group and a 1-hexenyl group.
  • alkynyl group examples include an ethynyl group, a 1-propynyl group, a 1-butynyl group, a 1-pentynyl group, a 3-pentynyl group and a 1-hexynyl group.
  • the “hydrocarbon group” represented by each of R 1 , R 2 and R 3 may or may not have a substituent.
  • substituents include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, a hydroxy group and a cyano group. Note that, the position of the substituent and the number of substituents are any position and number. If two or more substituents are present, the substituents may be the same or different.
  • the hydrocarbon group having a substituent is, in view of the RyR2 activity inhibitory effect, preferably a haloalkyl group such as a trifluoromethyl group, a pentafluoroethyl group and a 2,2,2-trifluoroethyl group.
  • the number of carbon atoms of an “alkoxy group” represented by each of R 1 and R 2 is, in view of the RyR2 activity inhibitory effect, preferably 1 to 6, more preferably 1 to 3, and particularly preferably 1.
  • the alkoxy group may be linear or branched. Examples of the alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group and a hexyloxy group.
  • the “alkoxy group” represented by each of R 1 and R 2 may or may not have a substituent.
  • Examples of the substituent are the same as those that the aforementioned hydrocarbon groups may have. Note that, the position of the substituent and the number of substituents are any position and number. If two or more substituents are present, the substituents may be the same or different.
  • the alkoxy group having a substituent is, in view of the RyR2 activity inhibitory effect, preferably a haloalkoxy group such as a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a pentafluoroethoxy group and a 2,2,2-trifluoroethoxy group.
  • the number of carbon atoms of an alkoxycarbonyl group, an alkanoyl group and an alkanoyloxy group represented by each of R 1 and R 2 is, in view of the RyR2 activity inhibitory effect, preferably 2 to 6, and more preferably 2 to 4.
  • the alkoxycarbonyl group, alkanoyl group, and alkanoyloxy group may be linear or branched.
  • an alkoxycarbonyl group is preferable, in view of the RyR2 activity inhibitory effect.
  • alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, a n-propyloxycarbonyl group, an isopropyloxycarbonyl group, a n-butoxycarbonyl group and a tert-butoxycarbonyl group.
  • alkanoyl group examples include an acetyl group and a propionyl group.
  • alkanoyloxy group examples include an acetoxy group and a propanoyloxy group.
  • examples of the substituent that the alkoxycarbonyl group, alkanoyl group and alkanoyloxy group may have are the same as those that the aforementioned hydrocarbon groups may have.
  • the position of the substituent and the number of substituents are any position and number. If two or more substituents are present, the substituents may be the same or different.
  • the halogen atom represented by each of R 1 and R 2 may be a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Of them, a fluorine atom is preferable.
  • R 1 and R 2 are, in view of the RyR2 activity inhibitory effect, preferably a substituted or non-substituted alkyl group having 1 to 8 carbon atoms, a substituted or non-substituted alkenyl group having 2 to 8 carbon atoms, a substituted or non-substituted alkoxy group having 1 to 8 carbon atoms, a substituted or non-substituted alkoxycarbonyl group having 2 to 3 carbon atoms, a hydroxy group, a cyano group, or a halogen atom; more preferably a substituted or non-substituted alkyl group having 1 to 8 carbon atoms, a substituted or non-substituted alkenyl group having 2 to 8 carbon atoms, a substituted or non-substituted alkoxy group having 1 to 8 carbon atoms, a substituted or non-substituted alkoxycarbonyl group having 2 to 8 carbon atoms,
  • the substitution position of R 1 may be on ring Q 1 .
  • the substitution position of R 1 is at least the 3-position.
  • the substitution position of R 2 may be on ring Q 2 .
  • ring Q 2 is a benzene ring and m is an integer of 1 to 5, it is preferable that the substitution position of R 2 is at least the 4-position.
  • R 3 represents, in view of the RyR2 activity inhibitory effect, preferably a hydrogen atom, a substituted or non-substituted alkyl group having 1 to 8 carbon atoms, or a substituted or non-substituted alkenyl group having 2 to 8 carbon atoms; more preferably a hydrogen atom, or a substituted or non-substituted alkyl group having 1 to 8 carbon atoms; further preferably a substituted or non-substituted alkyl group having 1 to 8 carbon atoms; further preferably a substituted or non-substituted alkyl group having 1 to 4 carbon atoms; and particularly preferably a methyl group.
  • R 4 represents a divalent hydrocarbon group having 1 to 8 carbon atoms.
  • the concept term of a divalent hydrocarbon group represented by R 4 includes a divalent aliphatic hydrocarbon group, a divalent alicyclic hydrocarbon group, and a divalent aromatic hydrocarbon group. Of them, a divalent aliphatic hydrocarbon group is preferable.
  • the divalent aliphatic hydrocarbon group may be linear or branched and saturated or unsaturated.
  • Examples of the divalent aliphatic hydrocarbon group include an alkanediyl group, an alkenediyl group and an alkynediyl group. Of them, in view of the RyR2 activity inhibitory effect, an alkanediyl group and alkenediyl group are preferable, and an alkanediyl group is more preferable.
  • the number of carbon atoms of an alkanediyl group is, in view of the RyR2 activity inhibitory effect, preferably 1 to 8, more preferably 1 to 4, further preferably 1 to 3, and particularly preferably 1.
  • the alkanediyl group include a methane-1,1-diyl group, an ethane-1,1-diyl group, an ethane-1,2-diyl group, a propane-1,1-diyl group, a propane-1,2-diyl group, a propane-1,3-diyl group, a propane-2,2-diyl group, a butane-1,1-diyl group, a butane-1,2-diyl group, a butane-1,3-diyl group, a butane-1,4-diyl group, a pentane-1,4-diyl group, a pentane-1,5-diyl group, a he
  • the number of carbon atoms of an alkenediyl group and an alkynediyl group is preferably 2 to 8, more preferably 2 to 4, and particularly preferably 2 or 3.
  • Examples of the alkenediyl group include ethylene-1,1-diyl group and an ethylene-1,2-diyl group.
  • Examples of the alkynediyl group include an acetylene-1,2-diyl group.
  • n and m each independently represent an integer of 0 to 5.
  • n and m may be an integer of preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 or 2.
  • n and m may be, in view of the RyR2 activity inhibitory effect, an integer of preferably 1 to 3, and more preferably, 1 or 2.
  • Compounds ( ⁇ 1) to ( ⁇ 12) include salts of the compounds represented by formulas ( ⁇ 1) to ( ⁇ 12).
  • the salts include alkali metal salts such as a sodium salt and a potassium salt; salts with a group-2 metal element such as a calcium salt and a magnesium salt; salts with a group-13 metal element such as an aluminum salt; ammonium salts; and organic amine salts such as a phenethylamine salt.
  • solvates thereof include a hydrate and solvates of alcohols.
  • Compounds ( ⁇ 1) to ( ⁇ 12) may sometimes have crystal polymorphic forms.
  • Compounds ( ⁇ 1) to ( ⁇ 12) may have a single crystal form or a mixture of a plurality of crystal forms. Alternatively, they may have amorphous form.
  • Compound ( ⁇ 2) is a compound represented by formula ( ⁇ 1) where n and m each represent an integer of 1 to 5.
  • a compound represented by formula ( ⁇ 3) is compound 39 later described in Examples; a compound represented by formula ( ⁇ 4) is compound 44 later described in Examples; a compound represented by formula ( ⁇ 5) is compound 61 later described in Examples; a compound represented by formula ( ⁇ 6) is compound 66 later described in Examples; a compound represented by formula ( ⁇ 7) is compound 40 later described in Examples; a compound represented by formula ( ⁇ 8) is compound 38 later described in Examples; a compound represented by formula ( ⁇ 9) is compound 59 later described in Examples; a compound represented by formula ( ⁇ 10) is compound 47 later described in Examples; a compound represented by formula ( ⁇ 11) is compound 37 later described in Examples; and a compound represented by formula ( ⁇ 12) is compound 41 later described in Examples;
  • Compound ( ⁇ 1) can be produced from a nitrile compound (CP1) and bromocarboxylic acid (CP6) used as starting materials by appropriate combination of methods commonly known and described, for example, in N. T. Pokhodylo, R. D. Savka, V. S. Matiichuk, and N. D. Obushak, A Study of Alkylation Regioselectivity of 5-Substituted Tetrazoles with Chloroacetamides; and Russian Journal of General Chemistry, 80, 836-841 (2010).
  • CP1 nitrile compound
  • CP6 bromocarboxylic acid
  • a compound ( ⁇ 1) represented by formula ( ⁇ 1) wherein Y is a nitrogen atom, X is an oxygen atom; and R 3 is a hydrogen atom, may be produced by
  • Step SA1-1> reacting sodium amide with a nitrile compound (CP1) in the presence of an amine salt to obtain a tetrazole derivative (CP2),
  • Step SA2> reacting the tetrazole derivative (CP2) and the amide derivative (CP4) in the presence of e.g., a strong base.
  • a compound ( ⁇ 1) represented by formula ( ⁇ 1) wherein Y is a methine group; X is an oxygen atom; and R 3 is a hydrogen atom, may be produced by
  • Step SB2> converting azidocarboxylic acid (CP7) obtained above into an acid chloride by use of oxalyl chloride and then amidating the acid chloride and an aniline derivative (CP8) by use of e.g., a base, to obtain an azide group-containing amide derivative (CP9), and
  • Step SB3> reacting the azide group-containing amide derivative (CP9) and an ethynyl compound (CP10) in the presence of a metal catalyst such as copper sulfate pentahydrate and sodium ascorbate.
  • a metal catalyst such as copper sulfate pentahydrate and sodium ascorbate.
  • a compound represented by the above formula ( ⁇ 1) or a salt thereof, or a solvate of the compound or a salt thereof, which can be produced as described above, has an excellent RyR2 activity inhibitory effect and is useful as a drug for preventing or treating diseases associated with abnormally elevated RyR2 activity.
  • the diseases associated with abnormally elevated RyR2 activity may be diseases caused by a RyR2 mutation (more specifically, activity-enhancing mutation) or diseases associated with abnormally elevated wild-type RyR2 activity.
  • diseases include arrhythmia, heart failure, cardiomyopathy, neurological disorder and Alzheimer's disease.
  • diseases caused by RyR2 activity-enhancing mutation include catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy and mental retardation.
  • Examples of the disease associated with abnormally elevated wild-type RyR2 activity include chronic heart failure associated with sympathetic tone in wild-type RyR2 and Alzheimer's disease.
  • the compound ( ⁇ 1) of the present invention is particularly useful as a drug for preventing or treating a disease selected from the group consisting of catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy, mental retardation, chronic heart failure and Alzheimer's disease.
  • a disease selected from the group consisting of catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, epilepsy, mental retardation, chronic heart failure and Alzheimer's disease.
  • the compound ( ⁇ 1) of the present invention can serve as a RyR2 activity inhibiter and a medicament for preventing or treating a disease associated with abnormally elevated RyR2 activity; and can be used for inhibiting RyR2 activity and preventing or treating a disease associated with abnormally elevated RyR2 activity and for producing a RyR2 activity inhibitor and a medicament for preventing or treating a disease associated with abnormally elevated RyR2 activity.
  • the term “use” may refer to administration to or ingestion by humans or non-human animals.
  • the RyR2 activity inhibitor and a medicament of the present invention may be applied by either a parenteral means such as injection, transrectal and topical administration or oral means.
  • the compound ( ⁇ 1) of the present invention may be used in combination with a pharmaceutically acceptable carrier and formulated into a pharmaceutical composition.
  • the pharmaceutically acceptable carrier include those commonly known in the technical field, such as an excipient, a binder, a buffer, a thickener, a stabilizer, an emulsifier, a dispersant, a suspending agent and a preservative.
  • the pharmaceutical composition can be prepared into drug preparations in accordance with a method commonly used in the technical field.
  • Examples of the drug preparations for oral administration include tablets (including sugar-coated tablets and film coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions and suspensions.
  • the drug preparation for oral administration can be produced by using additives commonly employed in the pharmaceutical field in accordance with a method commonly known.
  • the additives include excipients such as lactose, mannitol, anhydrous calcium hydrogen phosphate; binders such as hydroxypropyl cellulose, methyl cellulose and polyvinylpyrrolidone; disintegrants such as starch and carboxymethyl cellulose; and lubricants such as magnesium stearate and talc.
  • Examples of the drug preparation for parenteral administration include injections, rectal administration preparations and topical administration preparations. Of them, an injection is preferable.
  • Examples of the injections include an aseptic solution and suspension containing the compound ( ⁇ 1) of the present invention.
  • An injection can be produced, for example, by dissolving or suspending the compound ( ⁇ 1) of the present invention in water for injection according to the Japanese Pharmacopoeia.
  • An injection may contain, if necessary, a tonicity agent such as sodium chloride; a buffer such as sodium dihydrogen phosphate and sodium monohydrogen phosphate; and a dissolution aid.
  • an injection may be provided as a powder or lyophilized preparation, which is prepared into the injection when used by dissolving the preparation. In this case, a preparation can be produced using an excipient such as mannitol and lactose, in accordance with a common method.
  • rectal administration preparations examples include a suppository.
  • the suppository can be prepared, for example, by dissolving or suspending the compound ( ⁇ 1) of the present invention in a base such as cocoa butter and macrogol, and thereafter, pouring the solution or suspension in a template and molding it.
  • a rectal administration preparation can be produced by placing a solution or a cream in a container for injection.
  • Examples of dosage forms of topical administration preparations include a liquid, an eye drop, a cream, an ointment, a gel, a spray and a powder.
  • the liquid can be produced by adding the compound ( ⁇ 1) of the present invention in water and, if necessary, adding, e.g., a stabilizer, a dissolving agent, a thickener, a dispersant and a suspending agent.
  • a stabilizer e.g., a stabilizer, a dissolving agent, a thickener, a dispersant and a suspending agent.
  • the eye drop can be produced by adding, for example, the compound ( ⁇ 1) of the present invention, a buffer, a pH regulator, a tonicity agent and a preservative.
  • the cream and ointment can be produced by using, for example, the compound (l) of the present invention together with an aqueous or oily base (for example, water, liquid paraffin, vegetable oil (e.g., peanut oil, castor oil), macrogol).
  • an aqueous or oily base for example, water, liquid paraffin, vegetable oil (e.g., peanut oil, castor oil), macrogol.
  • the gel can be produced by using, for example, the compound ( ⁇ 1) of the present invention together with, e.g., gelatin, pectin, carrageenan, agar, tragacanth, an alginate, cellulose ether (e.g., methyl cellulose, sodium carboxymethyl cellulose), a pectin derivative, polyacrylate, polymethacrylate, polyvinyl alcohol and polyvinylpyrrolidone.
  • the compound ( ⁇ 1) of the present invention together with, e.g., gelatin, pectin, carrageenan, agar, tragacanth, an alginate, cellulose ether (e.g., methyl cellulose, sodium carboxymethyl cellulose), a pectin derivative, polyacrylate, polymethacrylate, polyvinyl alcohol and polyvinylpyrrolidone.
  • the spray can be prepared by dissolving or suspending, for example, the compound ( ⁇ 1) of the present invention in, e.g., water, and charging a spray container with the solution or suspension.
  • the compound ( ⁇ 1) of the present invention can be directly used or may be blended with an appropriate excipient.
  • the dose or injection amount of the RyR2 activity inhibitor or medicament of the present invention is determined in consideration of a target disease and symptom, and the age, body weight and sex of the subject to be administered.
  • the dose of the compound ( ⁇ 1) of the present invention is usually 0.01 to 100 mg, preferably 0.01 to 30 mg, and further preferably 0.1 to 10 mg per adult (body weight: about 60 kg) per day.
  • the dose can be administered or ingested once or divided into 2 to 4 portions and separately administered or ingested.
  • the dose of the compound ( ⁇ 1) of the present invention is usually 0.03 to 3000 ⁇ g, preferably 0.03 to 300 ⁇ g and more preferably 0.03 to 30 ⁇ g per adult/body weight (1 kg)/day.
  • the dose is administered once a day or divided into portions and separately administered.
  • Compound 1 was synthesized in accordance with the following synthetic pathway.
  • Compound 35 was synthesized in accordance with the following synthetic pathway.
  • Compound 66 was synthesized in the same operation as in Synthesis Example 35 except that n-propyl iodide was used in place of methyl iodide.
  • Compound 75 was synthesized in the same operation as in Synthesis Example 74 except that ethyl iodide was used in place of the methyl iodide.
  • cDNA of RyR2 was cloned from the heart muscle of a mouse by a PCR method and introduced into an expression vector (pcDNA5/FRT/TO) for Flp-In T-REX having hygromycin resistance.
  • the vector is a tetracycline-inducible expression (Tet-On) vector and induces expression of RyR in the presence of doxycycline.
  • R-CEPIA1er described in Nat. Commun., 2014, 5: 4153 was introduced into a neomycin resistant expression vector, pCMV/myc/ER. This vector constantly expresses R-CEPIA1er.
  • Flp-In T-REX 293 cells corresponding to the Tet-On inducible system were prepared. The cells were cultured in a CO 2 incubator at 37° C.
  • a pathogenic mutant-type RyR gene was introduced into Flp-In T-REX 293 cells by a lipofection method.
  • the cells were cultured in a medium containing hygromycin for 10 to 14 days to establish a pathogenic mutant RyR stably expressing strain.
  • an R-CEPIA1er expression vector was introduced by a lipofection method.
  • the strain was cultured in a medium containing G418 to establish a stable dual expression strain expressing a pathogenic mutant-type RyR gene and R-CEPIA1er.
  • a wild-type RyR gene was introduced into Flp-In T-REX 293 cells by a lipofection method.
  • the cells were cultured in a medium containing hygromycin for 10 to 14 days to establish a RyR stably expressing strain.
  • an R-CEPIA1er expression vector was introduced by a lipofection method.
  • the strain was cultured in a medium containing G418 to establish a stable dual expression strain expressing a wild-type RyR gene and R-CEPIA1er.
  • the cultured cells expressing a pathogenic mutant RyR and R-CEPIA1er and the cultured cells expressing wild type RyR and R-CEPIA1er were separately cultured in plastic dishes at 37° C. for 24 hours. Then, the medium was exchanged with a medium containing doxycycline and the cells were further cultured for 24 hours. Fluorescence measurement was carried out by use of FlexStation. R-CEPIA1er was excited at 560 nm to acquire fluorescence at 610 nm. Fluorescence was acquired every 10 seconds for 300 seconds. The compounds shown in Table 13 each were added 60 seconds after initiation, and Ca 2+ concentration in the fluorescent endoplasmic reticulum was measured.
  • mice Male mice administered with N-ethyl-N-nitrosourea (ENU) were crossed with normal wild type females to obtain child mice (First generation: G1). These G1 mice were subjected to systematic phenotypic screening. Mice exhibiting a heart disease phenotype were analyzed. As a result, a mouse having RyR2 I4093V mutation (RyR2 c.12277A>G (NM_023868.2) p.I4093V (NP_076357.2)) was found. The mouse was backcrossed with a normal wild type mouse (8 generations or more). As a result, mice conceivably having a mutation of RyR2 I4093V alone were obtained.
  • Compound 57 shown in Table 10 was dissolved in saline (0.9% aqueous NaCl solution) to prepare a 0.03-0.1 mg/mL solution containing compound 57.
  • mice of 4-5 months old were subjected to anesthesia induction with 2% isoflurane. While maintaining the anesthetic state with 1% isoflurane, electrodes for electrocardiogram were attached to four limbs and electrocardiographical monitoring was continuously carried out. Before drug administration, electrocardiographical monitoring was carried out for 10 minutes. Then, the solution containing compound 57 prepared above was intraperitoneally injected so as to have a concentration of 0.3 mg/kg or 1 mg/kg. The electrocardiogram was recorded for further 15 minutes.
  • FIG. 1 The results of a 0.3 mg/kg intraperitoneal injection case are shown in FIG. 1 .
  • bidirectional ventricular tachycardia periodically occurred before administration of compound 57.
  • ECG went back to normal by intraperitoneal administration of compound 57 (0.3 mg/kg).
  • FIG. 2 The results are shown in FIG. 2 . As shown in FIG. 2 , it is found that in a case where compound 57 is administered in a dose of 0.3 mg/kg or 1 mg/kg, occurrence of arrhythmia is low.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US17/760,419 2020-02-10 2021-02-10 Type 2 ryanodine receptor activity inhibitor Pending US20230150952A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2020-020656 2020-02-10
JP2020020656 2020-02-10
PCT/JP2021/005044 WO2021162054A1 (ja) 2020-02-10 2021-02-10 ２型リアノジン受容体活性抑制剤

Publications (1)

Publication Number Publication Date
US20230150952A1 true US20230150952A1 (en) 2023-05-18

Family

ID=77291800

Family Applications (1)

Application Number Title Priority Date Filing Date
US17/760,419 Pending US20230150952A1 (en) 2020-02-10 2021-02-10 Type 2 ryanodine receptor activity inhibitor

Country Status (4)

Country Link
US (1) US20230150952A1 (de)
EP (1) EP4104835A4 (de)
JP (1) JPWO2021162054A1 (de)
WO (1) WO2021162054A1 (de)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9823871D0 (en) * 1998-10-30 1998-12-23 Pharmacia & Upjohn Spa 2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents
GB9823835D0 (en) * 1998-10-30 1998-12-23 Univ London Component for vaccine
US6114365A (en) * 1999-08-12 2000-09-05 Pharmacia & Upjohn S.P.A. Arylmethyl-carbonylamino-thiazole derivatives, process for their preparation, and their use as antitumor agents
KR101771794B1 (ko) * 2015-08-04 2017-08-25 경북대학교 산학협력단 트리아졸로-아릴아크릴로나이트라일 유도체 및 이의 용도
JP6280536B2 (ja) 2015-12-11 2018-02-14 ヤンマー株式会社 トラクタ
ES2643856B1 (es) * 2016-05-24 2018-08-03 Universidad Del Pais Vasco / Euskal Herriko Unibertsitatea Triazoles para la regulación de la homeostasis de calcio intracelular
WO2019082940A1 (ja) 2017-10-25 2019-05-02 学校法人順天堂 リアノジン受容体阻害薬

Also Published As

Publication number Publication date
WO2021162054A1 (ja) 2021-08-19
JPWO2021162054A1 (de) 2021-08-19
EP4104835A1 (de) 2022-12-21
EP4104835A4 (de) 2024-05-01

Similar Documents

Publication Publication Date Title
RU2715421C2 (ru) Тетрагидропиранил амино-пирролопиримидинон и способы его применения
US11053207B2 (en) Indoleamine-2,3-dioxygenase inhibitor and preparation method therefor
US9708267B2 (en) Activators of human pyruvate kinase
JP6075621B2 (ja) 新規複素環誘導体およびそれらを含有する医薬組成物
US8471038B2 (en) Bicyclic heterocyclic compound
US8889702B2 (en) Derivatives of azaspiranyl-alkylcarbamates of 5-member heterocyclic compounds, preparation thereof and therapeutic use thereof
AU757290B2 (en) Imidazolone anorectic agents: II. phenyl derivatives
US20120184587A1 (en) Novel phenol derivative
JP2005523310A (ja) 置換インドール
US20110243844A1 (en) Sulfonamide derivative metabotropic glutamate r4 ligands
AU2006218125A1 (en) Pyrrolidine and piperidine acetylene derivatives for use as mGluR5 antagonists
TW202132304A (zh) 腺苷受體拮抗劑化合物
JP2012167027A (ja) Ｎｐｙｙ５受容体拮抗作用を有する縮合ヘテロ環誘導体
US20220389025A1 (en) Heterocyclic amide compound, pharmaceutically acceptable salt thereof, and preparation method therefor and use thereof
US20230150952A1 (en) Type 2 ryanodine receptor activity inhibitor
JP2010520255A (ja) ｍＧｌｕＲリガンドとしての縮合ピリミジノン化合物
US20240109863A1 (en) 2-pyridone derivative, and preparation method therefor and pharmaceutical application thereof
JP2016164154A (ja) オートタキシン阻害活性を有する７位無置換縮合ピラゾール誘導体
US7045516B1 (en) Benzoxazole derivatives and drugs containing the same as the active ingredient
EP0419286A2 (de) Pyridone nitrile verwendbar für die Behandlung kardiovaskularer Krankheiten
JPWO2017033966A1 (ja) オートタキシン阻害活性を有する５位カルボニルアミノアルキル置換縮合ピラゾール誘導体
JP3269658B2 (ja) フェノール誘導体
RU2747991C1 (ru) Тетрагидропиранил амино-пирролопиримидинон и способы его применения
JP2003081978A (ja) スピロ環式化合物およびその医薬用途
AU2021403606B2 (en) Chemical compounds useful for inhibiting nav1.8 voltage-gated sodium channels and treating nav1.8 mediated diseases

Legal Events

Date Code Title Description
AS Assignment

Owner name: JUNTENDO EDUCATIONAL FOUNDATION, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KUNIHIRO, NAGOMI KUREBAYASHI;MURAYAMA, TAKASHI;KAGECHIKA, HIROYUKI;AND OTHERS;SIGNING DATES FROM 20220725 TO 20220906;REEL/FRAME:061101/0934

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION